Amidinoureas and amidinothioureas

ABSTRACT

ANTIBACTERIAL AND ANTIFUNGAL MONO- AND DISUBSTITUTED AMINDINOUREAS AND AMIDINOTHIOUREAS ARE OBTAINED BY INTERACTION OF GUANIDINES AND ISOCYANATES OR ISOTHIOCYANATES.

United States Patent AMIDINOUREAS 6 Claims ABSTRACT OF THE DISCLOSURE Antibacterial and antifungal monoand disubstituted amidinoureas and amidinothioureas are obtained by interaction of guanidines and isocyanates or isothiocyanates.

This application is a division of our copending application Ser. -No. 749,986, filed Aug. 5, 1968, now US. Pat. 3,652,766, Mar. 28, 1972, which is a continuation-in-part of our now abandoned application Ser. No. 556,897, filed June 13, 1966, which in turn is a continuation-in-partof our now abandoned application Ser. No. 462,077, filed June 7, 1965. 1

This invention relates to chemical compounds classified as amidinoureas and amidinothioureas, to the preparation of the same and to a process for combatting microorganisms therewith.

The invention sought to be patented, in its process aspect, is described as residing in the concept of applying to a medium, in order to obviate objectionable or deleter'ious microorganisms, a composition of matter containing a chemical compound selected either from the group of compounds which, in the form of the free base, has the structural formula NH III R-NH-ii-NH-iJ-NH-R Formula I wherein X is a member of the group consisting of oxygen and sulfur and one of R and R is alkyl and the other of R and R is a member of the group consisting of hydrogen and alkyl, the total number of carbon atoms in R and R being 8-24; or from the group of compounds which, in the form of the free-base, has the structural formula NH x Y-NH-ii-NH-(H-NH-Y' Formula II wherein: X is a member of the group consisting of oxygen and sulfur; one of Y and Y is a'member of the group consisting of hydrogen, alkyl containing 1-18 carbon atoms, alkenyl containing 3-18 carbonatoms, alkoxyalkyl containing 3-17 carbon atoms, alkylthioalkyl containing "ice aspect, is described as residing in the concept of a chemical compound having the structural formula wherein: X is oxygen or sulfur; Y and Y' may be the same or different and are members of the group consisting of alkyl containing l-18 carbon atoms, alkenyl containing 3-18 carbon atoms, alkoxyalkyl containing 3-17 carbon atoms, alkylthioalkyl containing 3-17 carbon atoms, cycloalkyl containing 3-8 carbon atoms, di(lower alkyl)aminoalkyl containing 4-10 carbon atoms, morpholinoalkyl containing 6-10 carbon atoms or piperidinoalkyl containing 7-11 car-bon atoms; Y" also is hydrogen when X is oxygen and Y is alkenyl containing 3-18 carbon atoms, alkylthioalkyl containing 3-17 carbon atoms, di(lower alkyl)aminoalkyl containing 4-10 carbon atoms, morpholinoalkyl containing 6-1() carbon atoms or piperidinoalkyl containing 7-11 carbon atoms; and Y" also is hydrogen when X is sulfur and Y' is alkyl containing 8-18 carbon atoms, alkoxyalkyl containing 3-17 carbon atoms, alkylthioalkyl containing 3-17 carbon atoms, cycloalkyl containing 3-8 carbon atoms, di(lower alkyl)aminoalkyl containing 4-10 carbon atoms, morpholinoalkyl containing 6-10 carbon atoms or piperidinoalkyl containing 7-ll carbon atoms.

The compounds of Formulas I, II and III are basic substances which interact with one or, in the instances of the morpholinoalkyl and piperidinoalkyl compounds, two or three equivalents of an organic or inorganic acid to form the corresponding acid-addition salts. These acidaddition salts and the free bases of course have the common structural entity represented by the structural formulas, Formula I, Formula II, or Formula. III, as the case may be. The acid-addition salts are the full equivalents of the free base forms, and the new compounds of this invention include both the free bases and the acidaddition salts thereof. The novel feature of the compounds of the invention thus resides in the concept of the bases and the acid-addition salts thereof. The novel feature of the compounds of the invention thus resides in the concept of the bases and cationic forms of the new amidinoureas and amidinothioureas and not in any particular acid moiety or acid anion associated with the salt forms of our compounds; rather, the acid moieties or anions which can be associated in the salt forms are in themselves neither novel nor critical and therefore can be any acid anion or acid-like substance capable of salt formation with bases. It will be appreciated that in aqueous solutions the base form and the acid-addition salt form of the compounds of the inventioin possess a common protonated cation or ammonium ion.

Thus, the acid-addition salts discussed above and claimed herein are prepared from any organic acid, inorganic acid'(including organic acids having an inorganic group therein), or organo-metallic acid as exemplified by organic monoand poly-carboxylic acids such as found, for example, in Beilsteins Organische Chemie, 4th ed., volumes III, IV, IX, X, XIV, XVII, XIX, XXI, XXII, and XXV; organic monoand polysulfonic and -sulfinic acids such as found, for example in Beilstein volumes VI, XI, XVI, and XXII; organic phosphonic and phosphinic acids such as found, for example, in Beilstein volumes XI and XVI; organic acids of arsenic and antimony such as found, for example, in Beilstein volume XVI; organic heterocyclic carboxylic, sulfonic, and sulfinic acids such as found, for example in Beilstein volumes XVIII, XXII, and )OCV; acidic ion-exchange resins; and inorganic acids of any acid forming element or combination of elements such as found in Mellor, Comprehensive Treatise on Inorganic and Theoretical Chemistry, Longmans, Green and Co., New York, N.Y., volumes I-XVI. In addition, other salt-forming compounds which are acidic in their chemical properties but which are not generally considered as acids in the same sense as carboxylic or sulfonic acids are also considered to be among the numerous acids which can be used to prepare acid-addition salts of the compounds of the invention. Thus there are also comprehended acidic phenolic compounds such as found, for example, in volume VI or Beilstein, acidic compounds having activated or acidic hydrogen atoms, as for example, picrolonic acid, or barbituric acid derivatives having an acidic proton such as found, for example, in Cox et al. Medicinal Chemistry, vol. IV, John Wiley and Sons, Inc., New York, N.Y. (1959). Also comprehended as salt forming agents are so-called Lewis acids which lack a pair of electrons in the outer electron shell and react with basic compounds having an unshared pair of electrons to form salts, for example boron trifluoride.

Representative acids for the formation of the acid-addition salts include formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succinamic acid, glutamic acid, tartaric acid, oxalic acid, pyromucic acid, citric acid, lactic acid, glycolic acid, gluconic acid, saccharic acid, ascorbic acid, penicillin, benzoic acid, phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid, anthranilic acid, pamoic acid, cholic acid, Z-pyridinecarboxylic acid, 3-hydroxy-2-naphthoic acid, picric acid, quinic acid, tropic acid, 3-indoleacetic acid, barbituric acid, sulfamic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, butylarsonic acid, methanephosphonic acid, acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic acid, molybdic acid, arsenic acid, and the like.

The acid-addition salts are prepared in conventional fashion, for instance either by direct mixing of the acid and the base or, when this is not appropriate, by dissolving either or both of the acid and the base separately in a suitable solvent and mixing the two solutions, or by dissolving both the acid and the base together in a solvent. The resulting acid-addition salt is isolated by filtration, if it is insoluble in the reaction medium, or by evaporation of the reaction medium to leave the acid-addition salt as a residue.

Our new bases of Formulas I, II and III and the acidaddition salts thereof have biocidal and biostatic properties and are particularly useful as antibacterial and antifungal agents. Thus, when tested by standard serial dilution procedures, these compounds were found to have bactericidal, bacteriostatic, fungicidal, and fungistatic activity in vitro. Moreover, some of these compounds are effective in the control of phytopathogenic microorganisms, for instance, having useful activity against bacterial and fungal infections in plants, for example late blight (Phytophthora infestans) and bacterial spot (Xantomonas vesicatoria) on tomatoes (Lycopersicon esculenmm) and bean rust (Uromyces phaseoli typica) on pinto beans (Phaseolus vulgaris).

The new bases of Formulas I, II and III and the acidaddition salts thereof are useful as disinfecting and sanitizing agents for application to living and non-living surfaces by conventional swabbing, padding, spraying, immersing, rinsing, and the like techniques. Depending on the particular purpose involved, the compounds are used in aqueous solution, as in water or in aqueous detergent solutions, or in the form of solutions in organic solvents.

The acid-addition salts of the bases of Formulas I, II and III are useful not only as disinfecting and sanitizing agents, as above-indicated, but are also useful as characterizing or identifying derivatives of the free bases and in lsolation or urification procedures. Moreove e v 4 acid-addition salts react with strong bases, such as alkali metal hydroxides, to generate the free bases, and accordingly all of the salts, regardless of considerations of solubility, toxicity, physical form, or the like of a particular species of acid-addition salt, are useful for the purposes of our invention since they are sources of the free bases.

It will be appreciated from the above that if one or more of the characteristics, such as solubility, molecular Weight, physical appearance, toxicity, or the like of a given acid-addition salt render it unsuitable for the particular desired purpose, as for example, use as an antibacterial agent or in an isolation or purification procedure, or the like, the acid-addition salt can be converted to the free base and then to another, more suitable acid-addition salt, for instance a pharmaceutically-acceptable salt when a pharmaceutical use is involved.

The 1-(R)-amidino-3-(R')-ureas and the 1-(R)- amidino-3-(R)-thioureas of Formula I and the 1-(Y)- amidino'3-(Y)-ureas and the 1-(Y-amidino)-3-(Y')- thioureas of Formula II, except those species wherein R and Y are hydrogen, are obtained by interacting a l- (R)-guanidine or a 1-(Y)-guanidine with approximately one molecular proportion of an isocyanate or isothiocyanate having the structural formula R'NCX Formula IV for the preparation of the Formula I compounds and having the structural formula Y'NCX Formula V for the preparation of the Formula II compounds, wherein: R is hydrogen or alkyl and R' is alkyl, the total number of carbon atoms in R and R being 8-24;

Y is a member of the group consisting of hydrogen, alkyl containing 1-18 carbon atoms, alkenyl containing 3-18 carbon atoms, alkoxyalkyl containing 3-17 carbon atoms, alkylthioalkyl containing 3-17 carbon atoms, cycloalkyl containing 3-8 carbon atoms, di(lower alkyl) aminoalkyl containing 4-10 carbon atoms, morpholinoalkyl containing 6-10 carbon atoms, and piperidinoalkyl containing 7-11 carbon atoms; Y is a member of the group consisting of alkenyl containing 3-18 carbon atoms, alkoxyalkyl containing 3-17 carbon atoms, alkylthioalkyl containing 3-17 carbon atoms, cycloalkyl containing 3-8 carbon atoms, di(lower alkyl)aminoalkyl containing 4-10 carbon atoms, morpholinoalkyl containing 6-10 carbon atoms, and piperidinoalkyl containing 7-11 carbon atoms; and X in each instance is a member of the group consisting of oxygen and sulfur. In a convenient method of carrying out this reaction, sodium and dry acetone are mixed together, and then the guanidine in the form of its hydrochloride or sulfate is added, and this is followed by the isocyanate or isothiocyanate reactant; approximately equimolar amounts each of the sodium, the l-(R or Y)-guanidine salt, and the isocyanate or isothiocyanate are used, and the method can be carried out at room temperature.

The 1- (R)-amidino-3-(R')-ureas of Formula I Wherein R is hydrogen'and the l- (Y)-3-(Y')-ureas of Formula II wherein Y is hydrogen are obtained by hydrolyzing with a strong acid a 1-(R)-3-cyanoguanidine having the structural formula or a 1-(Y)-3-cyanoguanidine having the structural formula NH Y-NH-ii-NH-CN Formula. VII

wherein R is alkyl containing 8-24 carbon atoms and Y is a member'of the group consisting of alkenyl-containing 3-18 carbon atoms, alkoxyalkyl containing 3-17 carbon atoms, alkylthioalkyl containing 3-17 carbon atoms, cycloalkyl containing 3-8 "carbon atoms, di(lower alkyl)aminoalky1 containing 4-10 carbon atoms, mor pholinoalkyl containing 610 carbon atoms, and piperidinoalkyl containing 7-11 carbon, atoms. Conveniently, this hydrolysis is carried out by refluxing the .l-(R or Y),-- B-cyanoguanidine with concentrated hydrochloric acid.

The 1-(R)-amidino-3-(R)thioureas of Formula I wherein R is hydrogen and the 1-(Y)-amidino-3,-(Y')- thioureas of Formula H wherein Y is hydrogen are obtained by interacting one equivalent of a 1,(R)-3-cyanoguanidine having the structural Formula V or a 1-(Y)-3- cyanoguanidine having the structural Formula VI, as hereinabove defined, with two equivalents of hydrogen sulfide. Conveniently the cyanoguanidine is heated with a saturated lower alkanolic solution of hydrogen sulfide at 7080 C. in a closed vessel. For best results, the reaction mixture is heated for forty-eight hours or longer.

The 1-(Y")-amidino-3-(Y")ureas and the l-(Y")- amidino)-3-(Y"')-thioureas of Formula III are obtained by interacting a 1-(Y")-guanidine with approximately one molecular proportion of an isocyanate or isothiocyanate having the structural formula NCX Formula VIII wherein Y", Y'", and X have the same respective meanings indicated hereinabove in relation to Formula III. In a convenient method of carrying out this reaction, sodium and dry acetone are mixed together, and then the guanidine in the form of its hydrochloride or sulfate is added, and this is followed by the isocyanate or isothiocyanate reactant; approximately equimolar amounts each of the sodium, the 1-(Y")-guanidine salt, and the isocyanate or isothiocyanate are used, and the method can be carried out at room temperature.

The intermediates required for the preparation of our new compounds are all old and well-known classes of compounds are readily obtained by conventional preparative procedures. Thus, for example, the isocyanates and isothiocyanates of Formulas IV, V and VIII are obtained by interaction of phosgene or thiophosgene with a primary amine having the formula R'NH Y'-NH or Y'-NH or the hydrochlorides thereof, wherein R, Y', and Y'" have the same significance as indicated hereinabove in connection with Formulas IV, V and VIII. The 1-(R)-3-cyanoguanidines of Formula VI and the l-(Y)- S-cyanoguanidines of Formula VII are obtained, for example, by interaction of dicyanamide, or metal salt there of, with a primary amine having the formula RNH or Y-NH or acid-addition salt thereof, wherein R and Y have the same significance indicated hereinabove in connection with Formulas VI and VII, respectively. The l-(R, Y and Y")-guanidines include guanidine itself,

found to be particularly useful as antibacterial and antifungal agents. The chemical structures of the compounds of this invention followed from the modes of preparation from the elementary analyses of the products, and from spectral data on the compounds.

Our invention is illustrated by the following examples without, however, being limited thereto.

EXAMPLE 1 (A) 4.1 g. of sodium was added to 200 ml. of dry acetone and the mixture was refluxed for ten minutes and after the resulting mixture cooled to room temperature there was added in one portion, with strong stirring, 19.1 g. of guanidine hydrochloride. The resulting reaction mixture was stirred for forty-five minutes, and there was added dropwise, at room temperature and over a period of one-half hour, a solution of 23.2 g. of n-octyl isocyanate in 100 ml. of dry acetone. The reaction mixture thus obtained was stirred at room temperature for three hours and then was evaporated under reduced pressure to reduce its volume by half and poured into 250 ml. of cold water. (In following this procedure in the preparation of related species of this invention, it was found in some instances that instead of pouring the reaction product into water it was desirable and in some cases necessary for ready recovery of the product to evaporate the reaction mixture to dryness and then purify the resulting residue.) The mixture was chilled in a refrigerator overnight. The solid precipitate which formed was collected on a filter, Washed with cold water, and dried. The dry solid was dissolve in 250 ml. of warm diethyl ether, and the solution was treated with decolorizing charcoal and filtered. The filtrate was warmed to evaporate off about 100 ml. of ether and cold petroleum ether was added gradually until a slight turbidity was produced. The mixture was cooled andthe solid which precipitated was collected on a filter and dried in a vacuum desiccator. The solid thus obtained, which weighed 28.5 g., was recrystallized from diethyl ether-petroleum ether mixture to yield 24.1 g. of 1- amidino-S-n-octylurea, having the structural formula which is readily available, and the substituted guanidines which are obtained, for example, by interaction of ammoniuni chloride with a substituted cyanamide having the formula RNHCN, Y-NHCN or as a white crystalline solid which melted at l02l06 C. The solubility of this base in water at 25 C. was less than 0.25 percent. It was soluble in 95 percent ethyl alco hol at 25 C. to the extent of 5 percent (w./v.); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.

(B) When an equivalent amount of n-octyl isothiocyanate is substituted for the n-octyl isocyanate in the procedure described in Part A above, there is obtained as the product l-amidino-3-n-octylthiourea, having the structural formula (C) When an equivalent amount of iso-octyl isocyanate is substituted for the n-octyl isocyanate in the procedure described in Part A above, there is obtained as the product lamidino-3-iso-octylurea, having the structural formula NH cm i 4% 5 HzN- NH- NH-OHz-(GHrh- 11-03;

(D) When an equivalent amount of tert-octyl isothiocyanate is substituted for the n-octyl isocyanate in the procedure described in Part A above, there is obtained as the product 1-amidino-3tert-octylthiourea, having the structural formula CHr-CH:

(F) When an equivalent amount of 2-diethylarnioethyl isocyanate is substituted for the n-octyl isocyanate in the procedure described in Part A above, there is obtained as the product 1-amidino-3-(2-diethlaminoethl)urea, having the structural formula (G) When an equivalent amount of -morpholinoamyl isocyanate is substituted for the n-octyl isocyanate in the procedure described in Part A above, there is obtained as the product 1-amidino-3-(S-morpholinoamyl) urea, having the structural formula (H) When an equivalent amount of 3-piperidinopropyl isocyanate is substituted for the n-octyl isocyanate in the procedure described in Part A above, there is obtained as the product 1-amidino-3-(3-piperidinopropyl)urea, having the structural formula EXAMPLE 2 (A) Proceeding in a manner similar to that described above in Example 1, and using 3.2 g. of sodium, 14.3 g. of guanidine hydrochloride, and 18.3 g. of n-nonyl isocyanate, there was obtained 18.5 g. of l-amidino-3-nnonylurca, having the structural formula as a white crystalline solid which melted at 104-105 C.

The solubility of this base in water at 25 C. was less than 0.25 percent. In 95 percent ethyl alcohol at 25 C., it was soluble to the extent of 5 percent (w./v.); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.

(B) By treatment of l-amidino-S-n-nonylurea'with hydrobromic acid in isopropyl alcohol there was obtained l-amidino-B-n-nonylureau hydrobromide as a white crystalline solid which melted at 8082 C. This salt was soluble in water at 25 C. to the extent to 1 percent. The pH of the 1 percent solution was 4.7; when the pH was gradually raised by addition of N/ sodium hydroxide solution, a precipitate formed at pH 6.5.

(C) When an equivalent amount of iso-nonyl isothiocyanate is substituted for the n-nonyl isocyanate in the procedure described in Part A above, there is obtained as the product 1-amidino-3-iso-nonylthiourea, having the structural formula (A) Proceeding in a manner similar to that described above in Example 1, and using 3.2 g. of sodium, 14.3 g. of guanidine hydrochloride, and 18.3 g. of n-decyl isocyanate, there was obtained 17.5 g. of 1-amidino-3-ndecylurea, having the structural formula NH O HzN-i NH(!LL NHC Hz( C H2) s-C Ha as a White crystalline solid which melted at 1l0-112 C.

The solubility of this base in water at 25 C. Was less than 0.25 percent. In 95 percent ethyl alcohol at 25 C.,it was soluble to the extent of 5 percent (w./v.); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.

(B) The hydrobromide of the above base was prepared as follows: 10 g. of 1-amidino-3-n-decylurea was dissolved in ml. of warm methyl alcohol. The resulting solution was cooled to room temperature, and a solution of hydrogen bromide in diethyl ether was added until the pH of the mixture was approximately 6. The ether was evaporated 01f under reduced pressure, and to the oily residue'was added 200 ml. of anhydrous diethyl ether. The mixture Was filtered to collect the solid which formed. The solid thus collected, which weighed 12 g., was dissolved in 30 ml. of warm methyl alcohol, 400 ml. of anhydrous diethyl ether was added, and the mixture was cooled. The solid which precipitated from solution was collected on a filter; dried overnight in a vacuum oven at 35 C. There was thus obtained 9.4 g. of 1-amidino-3-n-decylurea hydrobromide as a white crystalline solid which melted at 78- 82 C. The solubility of this hydrobromide in water at 25 C. was 0.5 percent. The pH of the 0.5 percent aqueous solution was 5.0; when N/ 10 sodium hydroxide solution was gradually added to this solution, a precipitate formed at pH 5.5.

(C) To a solution of 17 g. of 1-amidino-3-n-decylurea in 150 ml. of methyl alcohol there was added 5 percent sulfuric acid until the pH of the mixture was approximately 3. The mixture was cooled, and the solid which precipitated was collected on a filter and recrystallized from ml. of methyl alcohol to yield 18 g. of l-amidino-S-n-decylurea sulfate which melted at 131-132" C. The solubility of this sulfate in water at 25 C. was less than 0.25 percent; and its solubility in percent ethyl alcohol at 25 C. was less than 1 percent (w./v.).

EXAMPLE 4 Proceeding in a manner similar to that described above in Part A of Example 1, and using 3.6 g. of sodium, 16.2 g. of guanidine hydrochloride, and 29.8 g. of n-decyl isothiocyanate, there was obtained 16.0 g. of 1-amidino-3-ndecylthiourea, having the structural formula as a white crystalline solid which melted at 71-72 C. The solubility of this base in water at 25 C. was less than 0.25 percent. In 95 percent ethyl alcohol, at 25 C. it was soluble to the extent of 5 percent (w./v.); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.

EXAMPLE 5 (A) Proceeding in a manner similar to that described above in Example 1, and using 4.3 g; of sodium, 19.1 g. of guanidine hydrochloride, and 29.6 g. of n-undecyl isocyanate, there was obtained 30 g. of 1-amidino-3-n-undecylurea, having the structural formula as a White crystalline solid which melted at 109-110" C. The solubility of this base in water at 25 C. was less than 0.25 percent. In 95.percent ethyl alcohol atv 25 C., it was soluble to the extent of 5 percent (w./v.); a precip itate formed when the percent alcoholic solution was diluted with four volumes of water. r

(B) By adding to a solution of g. of l-amidin6 3 n-undecylurea in 70 ml. of methyl alcohol sulficient ethereal solution of hydrogen bromide togive a mixture:havingpH 5, and isolating and recrystallizing the resultant product from methyl alcohol-diethyl ether mixture, there} was obtained 10.5 g. of 1-amidino-3-n undecylurea'hydrobromide as a white crystalline solid which melted at 82 83 C. The solubility of this hydrobromide' in water at 10 C. was less than 0.25 percent. Itwas soluble in 95 percent ethyl alcohol at 25 C. to the extent of 5 percent j (w.[v.);" a precipitate formed when the 5 percent alcoholiosolution was diluted with four volumes of water.

EXAMPLE 6 (A) Proceeding in a manner similar tothat described.

above in Example 1, and using 2.7 g. of sodium, 12.4 g. of

guanidine hydrochloride, and 21.1 g. of n-dodecyl isocyanate, there was obtained 23.0 g. of 1-amidino-3-n- 2 dodecylurea, having the structural formula v NH e H2N NHb I IH CH2(C H2)IFCHI I as a white crystalline "solid which melted at IOU-103 c. 25 The solubility of this base in water at 25 C. was less than 0.25 percent. Its solubility in 95 percent ethylalcohol at 25 C. was less than 1 percent (w./v.). he

Interaction of this base with hydrogen bromide yielded 1-amidino-3-n-dodecylurea hydrobromide as a white 0 crystalline solid which melted at 8789C. The solubility of this hydrob romide in water at 25C. was -lessthan 0.25; percent. It was soluble in 95 percent ethyl alcohol at.25 C. to the extent of 1 percent (w./v.);-no precipitate formed when the 1 percent alcoholic solution was diluted with four, volumes .of water, the pH of the thus-diluted-solution being EXAMPLE.7 Proceeding in a'manner similar to that describc d above in Example 1, and using 2.7 g.of "sodium, 12.4 g." or

guanidine hydrochloride, and 22.7 g. of ri-dodecylii'soth cyanate, there was obtained 12.8 g. of f1-ainidi'no 3 nf' dodecylthiourea, having the structural formula M NH s r HzN-(J-NH- NH'CHr-'(CH )m-GH; "I as a white crystalline solid which melted at 75-80 C. The solubility of this base in water at 25 C, was lessthan 0.25 percent. In 95 percent ethyl alcohol, at 25 C., it was soluble to the extent of 1 percent (w./v.); a precipitate. f:

formed when the 1 percent alcohilic solution was diluted with four volumes of water. 1

EXAMPLE :8"

10 as a white crystalline solid which melted at 77-79 C. The solubility'of this base in water was less'than 0.25 percent.

In 95 percent ethyl alcohol at 25 C., it was soluble to the extent of 5 percent (w./v.); a precipitate formed when--the'5; percent alcoholic-solution was diluted with four.- volumes of water.

EXAMPLE 9 :"(A Proceedingin a manner similar to that described above in Example 1, and using 3.4 g. of sodium, 15.3 g.

1 of -g"u'anidine*hydrochloride, and 30.1 g. of n-hexadecyl isocyanate,"-therewas obtained 23.7 g. of 1-amidino-3-nhexadecylurea, having the structural formula HzNC.-NHiJ-NHCH -(CH:)w-CPL.

N as a. white-crystalline solid which melted at 107-109 C.

The'solubility'of this base in water at 25 C. was less than 0.25 percent. Its solubility in 95 percent ethyl alcohol at 25 C. was less than 1 percent (w./v.).

(B) When an equivalent amount of n-hexadecyl isothiocyana'te'is substituted for the n-hexadecyl isocyanate in the'pr'o'cedure described in Part A above, there is obtained as the product l-amidino-3-n-hexadecylthiourea, having the structural formula H N iIJ-NH t i CH 2 a( :)1t CH:

EXAMPLE 10 *(A) Proceeding in a manner similar to that described I aboyeiin-Examplel, and using 3.2 g. of sodium, 14.3 g. of

guanidine, hydrochloride, and 18.1 g. of 9-decenyl isocyanate, there was obtained 16 g. of 1 amidino-3-(9- decenyl)urea,;-having the structural formula as a white crystalline solid which melted at 94-97 C. The solubility. of: this base in water; at 25 C. was less than 0.25; percent; In 95 percent ethyl alcohol at 25 C., it was soluble-to the extent of 5 percent (w./v.); a precipitate formed'when'the 5 percent alcoholic solution was diluted with, four volumes of water.

(B) When an equivalent amount of 9-decenyl isothiocyanate is substituted for the 9-decenyl isocyanate in the procedure described in Part A above, there is obtained as the product l-amidino-3-(9-decenyl)thiourea, having thestructuralformula- .7

HzN'-i") NHii,-NH CH1-.-(0H,)10 H=CH When an equivalent amount of 9-octadecenyl isocyanate is substituted for the 9-decenyl isocyanate in the procedure described in Part A above, there is obtained as (A) Proceeding in a manner similar to that described (B) Proceeding in a manner similar to. that described; in Example 1, and using 2.7 g. of sodium; 12.4 g.. of

guanidine hydrochloride, and 25.6 g. of n-tetradecyl iso- 7t) thiocyanate, there'was obtained 13.7 g. of l-amidino-3-ntetradecylthiourea, having thestructural formula ing tli'e'structural formula the product 1-amidino-3-(9roctadecenyl)urea, having the structural. formula 1 5131f U' HzN-ii--NH J--NHCH1(CH,)rCH=oH(cHi)9oH, (l '3 an eduivalent: amount of 9-octadecenyl isothiocyanate" issubstituted for the 9-decenyl isocyanate in thepro'ceduie described Part A above, there is obtained as the product 1-ainidino-?:(9-octadecenyl)thiourea, hav- EXAMPLE 11 d (A) Proceeding in a manner similar to that described abov'e'jiffExample 1, and using 2.72 g. of sodium, 12.2 g. of guanidihehydrochloride, and 18.0 g. of 3-(n-octyloxy) propyl iso'c ya'nate, there was obtained 4.0 'g.'- of 1-amidino 1 1 3 [3 (n-octyloxy)propyl]urea, havingthe structural formula r m I HzN-i Nii-NE-CH CH;CH,0CH (CH -CH, as an off-white powder which melted at 74-76 C. This base was soluble in a dilute acidic solution (prepared by mixing 0.36 ml. of N/ 2 hydrochloric acid and 0.14 ml. of water) at 25 C. to the extent of 10 percent. The pH of a 1 percent solution in the dilute acid was 2.2;no precipitate formed when the pH of this solution was adjusted to 7.0 by addition of N/ 10 sodium hydroxide solution. v A I (B) When an equivalent amount of 3-(n-octyloxy) propyl isothiocyanate is substituted for the 3-(n-octyloxy) propyl isocyanate in the procedure described in Part A above, there is obtained as the product 1-amidino-3- [3-(n-octy1oxy) propy1]thiourea, having the structural formula NH s HzN-JI J-NH-aNHCH:CHzCHr-OCHz(CHz)g-CH3 (C) When an equivalent amount of 6-methoxyhexyl isocyanate is substituted for the 3-(n-octyloxy)propy1 iso cyanate in the procedure described in Part A above, there is obtained as the product 1-amidino-3-(6-methoxyhexyl) urea, having the structural formula NH 0 H2N NH-i lNH-'-CHr-(CHz)4CH3-OCH3 (D) When an equivalent amount of 8-(n-propyloxy) octyl isothiocyanate is substituted for the 3-(n-octyloxy) propyl isocyanate in the procedure described in Part A above, there is obtained as the product 1-amidino-3-[8-(npropyloxy)octyl]-thiourea, having the structural formula (A) Proceeding in a manner similar to that described above in Example 1, and using 2.4 g. of sodium, 11.2 g. of guanidine hydrochloride, and 18.0 g. of 3-(n-decyloxy) propyl isocyanate, there was obtained 11 g. of l-amidino- 3-[3 (n decyloxy)propyl]urea, havingthe structural formula NH O EN-ii-NH-iil-NH-GH;CH;CH,OCHz-(CH2)o-CHI as a cream colored powder which melted at 78-82 C. The solubility of this base in water at 25 C. was less than 0.25 percent. In 95 percent ethyl alcohol at 25 C., it was soluble to the extent of percent (w./v.); avprecipitate formed when the 5 percent alcoholic solution was diluted with four volumes of Water. i a

(B) When an equivalent amount of 3- (n-decyloxy) propyl isothiocyanate is substituted for the 3-(n-decyloxy) propyl isocyanate in the procedure described in Part'A above, there is obtained as the product l-amidino-3-[3-(ndecyloxy)propyl]thiourea, having the structural formula EXAMPLE 13 (A) Proceeding in a manner similar to that described above in Example 1, and using 2.5 g. of sodium, 111 g. of guanidine hydrochloride, and 20 g. of 3-(n-decylthio):

propyl isocyanate, there was obtained 18.8 g. of l-ami- 12 dino3-[3-(n-decylthio)propyl]urea, having the structural formula NH. 0 h H2Ni J*-NH NH-CH2CH2CH2:S-CHz-(CHzh-CH; as a white solid which melted at 89-92 C. The solubility of this base in water at 25 C. was less than 0.25 percent. In percent ethyl alcohol at 25 C., it was soluble to the extent of 5 percent (w./v.); a precipitate formed 'when the Spercent alcoholic solution was diluted with four volumes of water.

(B) When an equivalent amount of 3-(n-decylthio) propyl isothiocyanate is substituted for the 3-(n-decylthio)propyl isocyanate in the procedure described in Part A above, there is obtained as the product l-amidino- 3-[3-(n-decylthio)propyl] thiourea, having the structural formula NH S 'HzNiiNHii NHOHzOH CHz-SCH(CH2) a-C H;

(C) When an equivalent amount of 4-(n-propylthio) butyl isocyanate is substituted for the 3-(n-decylthio) propyl isocyanate in the procedure described in Part A above, there is obtained as the product 1-amidino-3-[4- (n-propylthio)butyl]urea, having the structural formula NH O trate was obtained. The filtrate, which contained l-(ndecylamidino)urea hydrochloride dissolved therein, was.

cooled, and the pH was adjusted to approximately 6 by addition of N sodium hydroxide solution, thereby to neutralize the hydrochloride and generate the free base, 1-(n-decylamidino.)urea, having the structural formula and then a solution of 20 g. of sodium nitrate in 40 ml. of water was added with vigorous stirring. The mixture was chilled for several hours, and the solid which precipitated was collected on a filter and washed with dilute nitric acid and water. The solid was dried under reduced pressure at room temperature (about 25 C.) for four hours and at-30 C..for three hours. This product, which weighed 36 g., was recrystallized from 400 ml. of acetonitrile and then from 70 ml. of isopropyl alcohol to yield 12.0 g. of 1-(n-decylamidino)urea nitrate, as a white crystalline solid which melted at -l27 C. The solubility of this nitrate in water was less than 0.25 percent, and in 95 percent ethyl alcohol its solubility was less than 1 percent (w./v.-).

(B) When an equivalent amount of 1-n-octyl-3-cyanoguanidine is substituted for the 1-n-decyl-3-cyanoguanidine in the procedure described in Part A above, there are obtained as the products 1-(n-octy1amidino)urea, having the structural formula cyanoguanidine is substituted for the 1-n-decyl-3-cyanoand the nitrate salt thereof.

(B) When an equivalent amount of and the nitrate saltthereof.

. 13 guanidine in the procedure described in Part A above, there are obtainedas the products 1-(9 'decenylamidino) we: haves"r es fi mx i i l "decYl S-cyarioguanidine in -the-procedure described in PartA above, there are obtained as'the products 1-[4- (tert-octylthio)butylamidino1urea; having the structural formula CHI CH: CH:

,..(F). When an equivalent amount of 1-cyclooctyl-3- cyanoguanidine is suhstituted for the 1 -n-decyl-3-cyanoguanidinein the procedure described in Part Aabove, there are obtained as the products l-(cycloootylamidino) urea, having the structural formula GHQ-CH1 and the nitrate salt thereof. f a

(G) When ian equivalentamount 'l-(2morplidlino- -.1=-

ethyD-B-CyanOguanidine is substituted .jior the l-n-decyl- 3-cyanoguanidine in the procedure described in' Part 'A above, there are obtained as the products 1-[(2-morp'holinoethyl) a-midino]urea, having the structural formula and thejnitratesa'lt thereof.

(H)"Wl'1en' an equivalent amount of 1-(6-piperid inohexyl)-3-cyanoguanidine is substituted for the l-n-decyl- 3-cyanoguanidine in the procedure described in Part A above, there are obtained as the products 1-'[(6-piperidinohexyDamidinoJurea, hay in the structuralformula (HIP-CHI. if "onl n-om-rcrrm-onr-nn-b NH -b sn;

and the nitrate sailtthereofg EXAMPLE 1s Proceeding in a manner similar to that described above in Example 14, and using-25 .2 g.;ofl-n-dodecyl ii-cyanoguanidine, 68 -ml. of-isopropyl alcohoLand 16 ml. of concentrated hydrochloric acid, .there were; obtained 1'-(n-dodecylamidino)urea. hydrochloride, vthe tree base 1-(n-dodecylamidino)urea having the structural formula 0.25 percent, and in percent ethyl alcohol its solubility was less than 1 percent.

" EXAMPLE 16 and 1-(n-tetradecylamidino)urea nitrate. The nitrate (11 g. yield).\ was dissolved in methyl alcohol and sodium hydroxide solution was added to regenerate the free base, l-n-tetradecyl-3-cyanoguanidine, which was dissolved in methyl alcohol and treated with ethereal hydrogen bromide solution to yield 5.2 g. of 1-n-tetradecy1-3-eyanoguanidine hydrobromide as a white crystalline solid which melted at 116118 C. The solubility of the hydrobromide in water 25 C. was less than 0.25 percent. In 95 percent ethyl alcohol at 25 C., the hydrobromide was soluble to the extent of 5 percent (w./v.); a precipitate formed slowlywhen the 5 percent alcoholic solution was diluted with four volumes of water.

EXAMPLE 17 (A) A'mixture of 70 g. of 1-n-octyl-3-cyanoguanidine and 800 ml. of a saturated (at 0 C.) solution of hydrogen sulfide in methyl alcohol is heated at 70-80 C. in a closedvessel for forty-eight hours. The reaction mixture thus obtained is evaporated to dryness under reduced pressure leaving a residue consisting of crude l-(n-octylamidino) thiourea, having the structural formula Recrystallization of this product yields the pure base.

' When an equivalent amount of 1-n-heptadecy1-3- cyanoguanidine is substituted for the 1-n-octyl-3-cyanoguanidin'e in the procedure described in Part A above, there is obtained as the product 1(n hept-adecylamidino) v thiourfeahaving the structural formula (C) Whenan equivalent amount of 1-[6-(n-hexyloxy) hexyl]-3-cyanog'uanidine is substituted for the 1-n-octyl-3- cyanoguanidine'in the procedure described in Part A above, there is obtained as the product l-[fi-(n-hexyloxy) hexylamidino]thiourea, having the structural formula D) When an equivalent amount of 1- [b-(n-nonylthio) hexyl]-3-cyanoguanidine is substituted for the l-n-octyl-3- cyanoguanidine in the procedure described in Part A ab0v, there is obtained as the product l-[-(n-nonylthio) hexylamidinolthiourea, having the structural formula NH 5 om-(cH2)1CHls-oH,-(oH2)iCH2-NHb-NH-b-NH E) When an equivalent amount of l-(7-tetradecenyl)- 3-cyanoguanidine is substituted for the l-n-octyl-S-cyanoguanidinefin'the procedure described in Part A above, there is obtained as the product 1-(7-tetradecenyl)amidinothiourea, having the structural formula EXAMPLE 1s (A) To a solution obtained by dissolving 4.6 g. of sodium in 300 ml. of dry acetone there was added 32.8 g. of n-butylguanidine sulfate and the resulting" mixture was stirred for one hour at room temperaturejThere was then added dropwise, over a period of one hour,"a"solution of 19.8 g. of n-butyl isocyanate in 200 ml'r of-dry acetone, and the mixture thus obtained wasstirr'e'dovernight at room temperature. (In some iristances it was found preferable to use an equivalent amount of tert-butyl alcohol instead of acetone .both in the reaction with sodium and as the reaction solvent.) The reaction mixture was evaporated under reduced pressure.,.to"-reducepits volume by half, after which it was poured into 250 ml. of cold water. (In the preparation ofrelated speciesof this invention by this procedure, it was found-in some instances that instead of pouring the reaction product into water it was desirable and in some cases necessary. for ready recovery of the product to evaporate the reaction mixture to dryness and then purify the resulting residue.) The red oil which separated from solutionwas washed twice with water and was then dissolved in diethyl ether, The ethereal solution was dried over anhydrous-calcium sulfate, and the ether was then evaporated from the solu? tion to yield 1-n-butylamidino-3-n-butylurea, having the structural formula NH O as an oil. This base was dissolved in anhydrousidiethyl ether and was converted to its sulfate by addition of a percent ethereal sulfuric acid solution. The resultingammonia. The mixture was filtered to remove ammonium sulfate and the filtrate was evaporated under""reduc ed pressure to yield a red oil. This oil was dissolved 100 ml. of anhydrous diethyl ether, 75 ml. of petroleum ether was added, and the resulting solid precipitate was collected on a filter and dried under reduced pressure for four hours at 40 C. This product, which weighed 21.7 g., was recrystallized from benzene (100 ml .)-petroleum ether (80 ml.) and then from 700 ml..of,anhydrous d iethyl ether. There was thus obtained 10.3 'g, Ofl-IL-butYI- amidino-3-n-butylurea as a white crystalline solid which melted at 82-94" C. From the ethereal mother liquor there was recovered 3.1 g. of the same product. The solubility of this base in water was less than 0.5 percent. It was soluble in 95 percent ethyl alcohol to theextent of 5 percent (w./v.); on addition of four volumes'of water to the 5 percent alcoholic solution, the diluted solution, which had a pH of 8.9, remained clears: 1

(B) When an equivalent amount of n-butyl=.isothio-; cyanate is used in place of the n-butyl isocyanate in. the procedure described in Part A above, the productob-v tained is 1-n-butylamidino-3-n-butylthiourea, having the structural formula NH s (C) When an equivalent amount of 9-decenyl isocyanate is used in place of the n-butylisocyanate in the procedure described in Part A above, the"product""ob tained is 1-n-butylamidino-3-(9-decenyl)urea, havingthe' structural formula than the procedure. describe when an equivalent amount; of '4-morphplinobutylguaurdine sulfate is substituted'forthe"n butylguanidiiie'and an equivalent amount of cyclohexyl isocyanate is substituted forthe n butyl isocyanate, the product obtained is 1-(4-morpholinobtitylamidino) 3rcyclohexylurea, hat ing the structuralformula;

T .2 our-m (E) the .i'proc'edur'et. described "in .Part 5A; 'when an equivalent amount of l2-ethoxydodecylguanidine sul; fate-is substiIutcdfprthe n-butylgua v lentamount of .4f(n-oc tylthid)b utyl .1 so ;1 'anate v is, substi tuted for the n-butyl isocyanate, thel product c angers l-(l2 .ethoxydodecylamidino)-3 [4-(n octylthio)butylj as a white crystalline solid melted89-9l C. The solubility of this base in water at 25 C. was less than 0.25 percent. In percent ethyl alcohol at 25 C.

' it was soluble to the extent of '5fper'cent '(w./v.);' ap're;

ci'pi't'ate' formed when" the 5 'pe'rc'entf alcoholic solution was dilu'tedwithfour volumes of-water EXAMPLE 20;

Proceeding in a manner similar to that described above in PartA-offExample 18, and using' 4.5 g. of sodium, 38.4 g. of n-hexylguanidine sulfate, and 19.8 g. of nbutyl isocyanate, there was obtained 'z'r'gsbr l-n-hexyli1 amidin o lin butylurea having the jstfucturalformula as "an air-white crystalline powder which melted "at 96 I a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes ofwater;

Exams-re at Proceeding aimanner. similar ,towthat-described above in- Part A of-Example 18, and;.,usin g 3.44 g. of sodiurn 28,-.8 g. of nrhexy'lguanidine sulfate, and 1 17.0,. g. -of. r1; my o y n t er -w ob ai d-20.9 s. lrl r il fiy amidino-i-n-amyl a. a e str ctural-for a NH 0 outoHnFom n m-ii Nfi-ii' NH- QH OHm-CH.

as white; crystalline The solubility of this base ,infwater' lat, 25 C. "wasfl'e ss than 0.25 percent. In 95 percent ethyl'alcohol'at 25 'C.

. 1'7 1 it was soluble to the extent of percent (w./v.); a precipitate formed when the 5 percent alcoholic solutionwas diluted with four volumes of water.

EXAMPLE 22 (A) Proceeding in a manner similar to that described above in Part A of Example 18, and using 4.5 g. of sodium, 38.4 g. of n-hexylguanidine sulfate, and 25.4 g. of n-hexyl isocyanate, there was obtained 11.1 g. of l-nhexylamidino-3-n-hexylurea having the structural formula as a white crystalline solid which melted at 75-78 C. The solubility of this base in water at 25 C. was less than 0.25 percent. In 95 percent ethyl alcohol at 25 C. it was soluble to the extent of 5 percent (w./v.); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.

(B) By treatment of 6 g. of 1-n-hexylamidino-3-n-hexylurea with hydrogen chloride in methanolic solution there was obtained 6.3 g. of 1-n-hexylamidino-3-n-hexylurea hydrochloride as a white crystalline solid which melted at 60-62 C. The solubility of this hydrochloride in water at 25 C. was less than 0.25 percent. It was soluble in 95 percent ethyl alcohol at 25 C. to the extent of 5 percent (w./v.); a precipitate formed slowly when the 5 percent alcoholic solution was diluted with four volumes of water, the pH of the thus-diluted solution being 4.4.

(C) By treatment of 6 g. of 1-n-hexylamidino-3-n-hexylurea in methanolic solution with an ethereal solution of hydrogen bromide there was obtained 6.5 g. of l-n-hexylamidino-S-n-hexylurea hydrobromide as awhite crystalline solid which melted at 56-60 C. The solubility of this hydrobromide in water at 25 C. was less than 0.25 percent. It was soluble in 95 percent ethyl alcohol at 25 C. to the extent of 5 percent (w./v.); a precipitate formed slowly when the 5 percent alcoholic solution was diluted with four volumes of water, the pH of the thus-diluted solution being 4.3.

(D) By treatment of 6 g. of 1-n-hexylamidino3-n-hexylurea with 85 percent phosphoric acid in methanolic solution there was obtained 6.2 g. of 1-n-hexylamidino-3- n-hexylurea phosphate as a white crystalline solid which melted at 106109 C. The solubility of this phosphate in water at 25 C. was less than 0.25 percent. It was soluble in '95 percent ethyl alcohol at 25 C. to the extent of 5 percent (w./v.); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.

(E) By treatment of 6 g. of l-n-hexylamidino-3-n-hexylurea with 70 percent glycolic acid in methanolic solution there was obtained 5.5 g. of l-n-hexylamidino-3-nhexylurea glycolate as a white crystalline solid which melted at 9498 C. The solubility of this glycolate in water at 25 C. was less than 0.25 percent. It was soluble in 95 percent ethyl alcohol at 25 C. to the extent of 5 percent (w./v.); a precipitate formed when the 5 percent alcoholic solution was diluted'with four volumes of water.

(F) By treatment of 6 g. of 1-n-hexylamidino-3-n-hexylurea with 85 percent lactic acid in methanolic solution there was obtained 5 g. of 1-n-hexylamidino-3-n-hexylurea lactate as a white crystalline solid which melted at 65-69" C. The solubility of this lactate in a dilute acidic solution (prepared by mixing 0.28 mlrof N/2 hydrochloric acid solution with 19.72 ml. of water) at 25 C. was less than 0.25 percent. It was soluble in 95 percent ethyl alcohol at 25 C. to the extent of 5 percent (w./v.); a precipitate formed when the 5 percent alcoholic solution was diluted withfour volumes of water.

I EXAMPLE 23 I Proceeding in a manner similar to that described above in Part A of Example 18, and using 3.44 g. of sodium,

30.9 g. of n-heptylguanidine sulfate, and 19.1 g. of nhexyl isocyanate, there was obtained 26.2 g. of l-n-heptylamidino-3-n-hexylurea having the structural formula as a white crystalline solid which melted at 6872 C.

The solubility of this base in a dilute acidic solution (prepared by mixing 0.36 ml. of N/2 hydrochloric acid and 9.64 ml. of water) at 25 C. was less than 0.25 percent. In percent ethyl alcohol at 25 C. it was soluble to the extent of 5 percent (w./v.)', a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.

EXAMPLE 24 Proceeding in a manner similar to that described above in Part'A of Example 18, 2.7 g. of sodium was dissolved in 250 ml. of dry acetone, 25 g. of n-heptylguanidine sulfate was added to the solution, the mixture was stirred for fifteen hours at room temperature; and thena solution of 16.9 g. of n-heptyl isocyanate in 200 ml. of acetone was added dropwise, and the reaction mixture was stirred for three hours at room temperature. The reaction mixture was evaporated to half-volume under re duced pressure and the mixture was stored in a refrigerator for two weeks. The solid which had precipitated was collected on a filter, was washed with water and a few ml. of acetonitrile, and dried overnight in a desiccator. The yellowish product thus obtained, which weighed 32.2 g., was mixed with 30 ml. of cold acetonitrile, and the solid was collected on a filter, dried overnight in a desiccator, and then recrystallized from acetonitrile to yield 23 g. of l-n-heptylamidino 3 n heptylurea having the structural formula CH,-(CHz)s-CH,NHyJ-NBF-i'l-NH-Cfir-(CHM-CH; as a white crystalline solid which melted at 56-59" C. This base in methanolic solution was treated with ethereal hydrogen chloride solution to yield 21.3 g. of l-n-heptylamidino-3-n-heptylurea hydrochloride as a white crystalline solid which melted at 7175 C. The solubility of this hydrochloride in dilute aqueous alkali (prepared by mix- 7 ing 0.30 ml. of N/2 sodium hydroxide solution with 19.70

EXAMPLE 25 (A) 3.68 g. of sodium and 1050 ml. of dry t-butyl alcohol were heated together under reflux with vigorous stirringfor about two hours. The liquid was cooled to approximately 28 C. and then 25 g. of (3 morpholinopropyl)-guanidine sulfate was added in one portion. After stirring the mixture for thirty minutes, a solution of 9.85 g. of n-octyl isocyanate in ml. of t-butyl alcohol was added dropwise .over a period of twenty minutes. The resulting reaction mixture was stirred for two and one-half hours and allowed to stand overnight. The mixture was concentrated on a water bath at 35-45 C. The residue was mixed with 250 ml. of acetonitrile and allowed to stand overnight. The mixture was filtered to remove 16.2 g. of solid, and the acetonitrile was distilled from the filtrate to yield 23 g. of a light-brown syrup consisting of crude 1-[(3-morpholinopropyl)amidino]-3 n-octylurea, having the structural formula solid Which had precipitated was then collected on-a filter.

This solid, which-weighed 17.7 g., was recrystallized from isopropyl alcohol, with charcoaling, to yield 12.8 g. of solid, which was then recrystallized again from isopropyl alcohol. There was thus obtained 9.5 g. of 1-[(3-m'orpholinopropyl)amidino]-3-n-octylurea dihydrochloride as a white powder which melted at 141-143 C. (dec.). This salt was soluble in:water at 25 C. to the extent of 20 percent. The pl-l of the l-percnt aqueous solution was 4.0; when the pH of this solution was gradually raised was by addition'of N/ sodium hydroxide solution, no precipitate formedat pI-I'7. a

(B) When an equivalent amount of (2-piperidinoethyl)guanidine sulfate is used-instead of (3-morpholinoprOpyDgua-nidine sulfate in the procedure described in v;Part-Aabove, the products obtained are 1-[(2 -piperidinoethyl)amidino1-3-n-octylurea, having the structural for mula I our-on, NH- 0 and the dihydrochloride thereof. HI C) Following the procedure described in Part A above but using an equivalent amount of 4-piperidinobutyl isocyanate in place of n-octyl isocyanate, there are obtained as the products 1-[(3-morpholinopropyl)amidino]-3-'(4- piperidinobutyl)-urea, having the structural formula and the trihydrochloride thereof.

' EXAMPLE 26 Proceeding in a manner similar to that described above 25 g. of (3-morpholinopropyl)guanidine sulfate, and 11.6

r g. of n-decyl isocyanate, there were obtained 1 -[(3-m orpholinopropyl)amidino]-3-n-decylurea having the structural formula andthe dihydrochloride thereof. The dihydrochloride was:2.- obtained as a White powder which weighed 152 gaand which melted at 134-135 C. This salt wasgsoluble in water at 25 C. to the extent of 20 percent; the pH of the 1 percent aqueous solution was 4.6 and when the pH was gradually raised by addition of N/ IO. sodium hy-l droxide solution no precipitate formed at pH 7.

" EXAMPLE 27 Proceeding in a manner similar to that described'above in Example 18A, and using 2.3 g. of sodium, 22 g. of

n-octylguanidine sulfate, and 15.5 g. of n-octyl isocyanate,

lthere'was obtained 26 g'. of 1-n-octylarnidino-3-n octylurea having the structural formula NH 0 v CH;-(CHzh-OHy-NH-iil-NHH3NHCH2(CHz)o-CHa as a white crystalline solid which melted at 60-629 C.

The solubility of this base in water at 25 C. was less than 0.25 percent. In 95 percent ethyl alcohol it' was soluble V in Part A of Example 25, and using 3.68 g. of sodium,

to the extent of5 percent; a precipitate formed when the 5 percentethanolic solution was diluted with four volumes of water. EXAMPLE 28 (A) Proceeding ina manner similar to that described above in Example 1, and using 3.4 g. of sodium, 14.3 of guanidine hydrochloride, and 27.7 g. of n-nonyl isothiocyanate; there was obtained 1ramidino-3-n-nonylthiourea, having the structural formula (B) By treatment of l-amidino-3-n-nonylthiourea with ethereal hydrogen chloride. there was obtained'lramidino- 3-n-nonylthiourea hydrochloride as a white crystalline solid which melted at 798l C. The solubility of this salt in water at 25C. was less than 0.25 percent; andits solu bility in pergent ethyl alcohol at 25 C. was less than lpercent (w./v.). .v

. EXAMPLE 29 ,j

Proceeding in a manner similar to'thatdescribed above 'in 'ExampleLand using 2.5 g. of sodium, 10.4 of guanidine hydrochloride, and 24.5 g. of n-undecyl isothiocyanate,

there was obtained 15.9 g. of l-amidino-S-n-undecylthiourea, having the structural formula a VI IH S ngN t i-mn-g-un -omsunken.

as a white crystalline solid which melted at 7172 C.

'The solubility of this base in a dilute acidic solution (0.40

ml. of N/2 hydrochloric acid plus 19.60 ml. of water) was less than 0.25 percent. In 95 percent ethyl alcohol at 25 C., it was soluble to the extent of less than 1 percent 7 v V I EXAMPLE30 Proceeding in a manner. similar to that described above j in 'Examplel, and using 2.9 g. of sodium, 12.9 g. of guani- V 1 5 on o'r r,

dine hydrochloride, and 17.9 g. of 3-(n-heptyloxy) -propyl isocyanate, there was obtained 1-amidino-3-[-3-(n-heptylo x y)propyl]-urea, having the structural formula as a white powder which melted at 72-74 C. This base was soluble in a dilute acidic solution (0.39 ml. of N/2 hydrochloric acid plus- 0.61 ml. of-water) 'at 25 f C. to the extent of-5 percent. In 95 percent ethyl alcohol at 25 C.,

it was solubleto the extent of 5 percent (W./v.); a precipitateformed when the 5 percent alcoholic'solution was diluted with four volumes of water.

EXAMPLE 31 propyl isocyanate, there was obtained 1-amidino-3-[3-(nnonyloxy)propyl]urea having the structural formula as awhite crystalline solid which melted at 77-78 C. This base was soluble in adilute acidic solution (0.35 ml. of hydrochloric acid plus 19.65' ml. of water) to less v than 0.25 percent. In 95 percent ethyl alcohol at 25 C., it

was" soluble to the extent of 5 percent (w./-v.); a precipi- 'tate formed when the 5 percent alcoholicsolution was diluted with four volumes of water.

EXAMPLE 32 (A) Proceeding in a manner similar to that described above in Example 1, andus ing 2.8 g. of sodium, 12.0 g. of

21 guanidine hydrochloride, and 32.0 g. of 3-(n-undecyloxy)- propyl isocyanate, there was obtained 15.7 g. of l-amidinoas a white powder which melted at 727 8 C.

3-[3-(n-undecyloxy)propyl]urea, having the structural (B) Interaction of this base with hydrogen chloride yielded 1- amidino-3-[3-(n-undecyloxy)propyl]urea hydrochloride as a white powder which melted at 66-69 C. This hydrochloride was soluble in water at 25 C.- to the extent of 20 percent-The pH of a 1 percent aqueous solution was 3.7; when N/ sodium hydroxide solution was gradually added to this solution, a precipitate formed at pH 5.5. v

1 EXAMPLE 33 (A) Proceeding in a manner similarto that described above in Example 1, and using 3.0 g. of sodium, 13.0 g.

of guanidine hydrochloride, and 36.6 g. of 3-(n-dodecyloxy)propyl isocyanate, there was obtained 1-amidino-3- [3-(n-dodecyloxy)propyl]urea, having the structural formula.

NH O

EXAMPLE 34 Proceeding in a manner similar to that described above in Example 1, and using 2.3 g. of sodium, 9.5 g. of guanidine hydrochloride, and 20.0 g. of 3-(n-hexylthio)propyl isocyanate, there was obtained 1-amidino-3-[3-(nhexylthio)propyl]urea, having the structural formula as a white crystalline solid which melted at 7l-73 C.

The solubility of this base in a dilute acidic solution (0.78 ml. of N/2 hydrochloric acid plus 19.72 ml. of water) at 25 C. was less than 0.25 percent. In 95 percent ethyl alcohol at 25 C., it was soluble to the extent of 5 percent (w./v.); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.

EXAMPLE 35 Proceeding in a manner similar to that described above in Example 1, and using 1.06 g. of sodium, 4.45 g. of guanidine hydrochloride, and 10.0 g. of 3-(n-heptylthio) propyl isocyanate, there was obtained l-amidino-3-[3-(nheptylthio)propyl]urea having the structural formula as a white crystalline solid which melted at 79-82 C.

The solubility of this base in a dilute acidic solution (0.40 ml. of N/2 hydrochloric acid plus 19.60 ml. of water) at 25 C. was less than 0.25 percent. In 95 percent ethyl alcohol at 25 C., it was soluble to the extent of 5 percent (w./v.); a precipitate formed when the 5 per- 'cent alcoholic solution was diluted with four volumes of Water.

EXAMPLE 36 Proceeding in a manner similar to that described above in Example 1, and using 3.4 g. of sodium, 14.3 g. of guanidine hydrochloride, and 34.3 g. of 3-(n-octylthio)- propyl isocyanate, there was obtained 22.0 g. of l-amidino-3-[3-(n-octy1thio)propyl]urea having the structural formula as a white crystalline solid which melted at 84-85 C. The solubility of this base in a dilute acidic solution (0.35 ml. of N/2 hydrochloric acid plus 19.65 ml. of water) at 25 C. was less than 0.25 percent. In percent ethyl alcohol at 25 C., it was soluble to the extent of 5 percent (w./v.); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.

EXAMPLE 37 Proceeding in a manner similar to that described in Example 1, and using 2.3 g. of sodium, 9.5 g. of guanidine hydrochloride, and 22.9 g. of 3-(nnonylthio)propyl isocyanate, there was obtained 19.7 g. of l-amidino-3- [3-(n-nonylthio)propyl]urea, having the structural formula as a 'white crystalline solid which melted at 86-88 C. The solubility of this base in a dilute acidic solution (0.34 ml. of N/ 2 hydrochloric acid plus 19.66 ml. of water) at 25 C. Was less than 0.25 percent. In 95 percent ethyl alcohol at 25 C., it was soluble to the extent of 5 percent (w./v.); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.

EXAMPLE 3 8 Proceeding in a manner similar to that described above in Example 1, and using 2.3 g. of sodium, 9.5 g. of guanidine hydrochloride, and 27.1 g. of 3-(n-undecylthio)-propyl isocyanate, there was obtained 16.6 g. of 1-amidino-3-[3-(n-undecylthio)propyl]urea, having the structural formula .as a white crystalline solid which melted at 9193 C.

The solubility of this base in a dilute acidic solution (0.30 ml. of N/2 hydrochloric acid plus 19.70 ml. of water) at 25 C. was less than 0.25 percent. In 95 percent ethyl alcohol at 25 C., it was soluble to the extent of 5 percent (w./v.); a precipitate formed when the 5 percent alcoholic solution was diluted in four volumes of water.

EXAMPLE 39 Proceeding in a manner similar to that described above in Example 1, and using 2.3 g. of sodium, 9.5 g. of guanidine hydrochloride, and 28.5 g. of 3-(n-dodecylthio)-propyl isocyanate, there was obtained 28.5 g. of 1-amidino-3-[3-(n-dodecylthio)propyl]urea, having the structural formula as a white crystalline solid which melted at 91-92 0. The solubility of this base in a dilute acidic solution Proceeding in a manner similar to that described above in Part A of Example 25, and using 1.96 g. of sodium, 12.5 g. (3-morpholinopropyl)guanidine sulfate, and 7.2 g. of n-nonyl isocyanate, there was obtained 1-[(3-morpholinopropyl)amidino]-3-n-nonylurea having the structural formula GHQ-CHI NH O and the dihydrochloride thereof. The dihydrochloride was obtained as a white powder which melted at 139-141 C. This salt was soluble in water at 25 C. to the extent of 20 percent; the pH of the 1 percent aqueous solution was 3.5, and when the pH was gradually raised by addition of N/ sodium hydroxide solution, no precipitate formed at pH 7.

EXAMPLE 41 Proceeding in a manner similar to that described above in Part A of Example 25, and using 1.96 g. of sodium, 12.5 g. of (3-morpholinopropyl)guanidine sulfate, and 8.4 g. n-undecylisocyan-ate, there was obtained 1- [(3- morpholinopropyl)amidino]-3-n-undecylurea having the structural formula and the dihydrochloride thereof. The dihydrochloride was obtained as a white powder which weighed 9.7 g. and which melted at 143145 C. The salt was soluble in water at 25 C. to the extent of percent; the pH of-the 1 percent aqueous solution was 3.8, and when the pH was gradually raised by addition of N/ 10 sodium hydroxide solution, no precipitate formed at pH 6.3.

EXAMPLE 42 Proceeding in a manner similar to that described above in Part A of Example 25, and using 1.96 g. of sodium,

12.5 g. of (3-morpholinopropyl)guanidine vsulfate, and" 8.95 g. of n-dodecylisocyanate, there was obtained l-[ (3- morpholinopropyDamidino]-3-n-dodecylurea having the structural formula and the dihydrochloride thereof. The dihydrochloride was obtained as a white powder which weighed 5.9 g. and

which melted at 132-135 C. This salt was soluble inwater at C. to the extent of 20 percent; the pH of the 1 percent aqueous solution was 3.8, and when the pH was gradually raised by addition of N/10 sodium hydroxide solution, no precipitate formed at pH 7.6.

24 Proceeding in accordance with the procedures described hereinabove and using the appropriate reactants, there are obtained the following further illustrative species of the compounds of Formulas I, II and III of the instant invention:

( 1 l-n-hexylamidino-3- (3 ,3-dimethylallyl)urea (2) 1-(4-dimethylaminobutylamidino -3-cyclopropylurea (3) 1- (9-decenylamidino) -3- (9-decenyl) urea (4) l-cyclohexylamidino-3-cyclopentylurea (5 1-cycloheptylamidino-3- [4- (n-arnyloxy) butylJurea (6) 1- 3-morpholinopropylamidino -3- (3-octenyl) thiourea (.7) 1-(3-piperidinopropy1amidino) -3-(3- piperidinopropyl) thiourea (8 l-n-hexylamidino-S -n-hexylthiourea (9) 1-n-heptylamidino-3 -n-heptylthiourea 10) l-tert-octylamidino-3- 3-morpholinopropyl) urea (11) 1- 3- (n-octyloxy) propylamidino] -3- (3- morpholinopropyl urea (12) 1-(cyclobutylamidino)-3- [3- (n-decyloxy)propyl] thiourea 13 1- 8-dimethlaminooctylamidino) -3- [3- (n-decylthio) propyl] -thiourea 14) l-n-octylamidino-3- (3-propoxypropyl)urea 15 1-iso-heptylamidino-3- [4- (propylthio) butyl] urea l 6) 1-n-heptylamidino-3- (2-diisopropylaminoethyl) thiourea 17 1-cyclopentylamidino-3-n-undecylurea 18) l-cyclopropy1amidino-3- (3-piperidinobutyl)urea 19) 1- 3-morpholinopropylamidin0) 3- (4- morpholinobutyl) urea (20) l- Z-diethylaminoethylamidino )-3- (2- diethylaminoethyl) thiourea (21) 1- (Z-dimethylaminopropylamidino -3- 3- morpholinopropyl) thiourea (22) 1- 3- (n-decylthio) propylamidino]-3- [3- (ndecylthio)propyl] urea (23 1- [3- (n-decylthio propylamidino] -3-cyclohexylurea (24) 1- [4- (n-nonylthio butylamidino] -3- (5- morpholinoamyl) urea (25 1- [3- (n-octyloxy) propylamidino]-3- [3- (n-octyloxy) propyl] urea (26) 1- [3-(n-heptyloxy)propylamidino]-3-(10-undecenyl)urea I 27) l-cyclopentylamidino-B- 3,3-dimethylallyl) urea (28) 1[ (3-hexenyl) amidino] -3- [3- (n-dodecylthio) propyl]urea (29) 1-( 3-di-n-butylaminopropylamidino) -3-(4-octenyl) urea (30) 1-metha1lylamidin0-3- (3-piperidinopropyl)urea (3 l 1 -(2-piperidinoethylamidino)-3 (3-diethy1amin0- propyl) thiourea (32 !1- 3 piperidinopropylamidino) -3- [4-'(n-propyloxy) butyl1urea (33) 1-methylamidino-3-(2-ethylhexyl)urca 34) '1-ethylamidino-3-isohexylthiourea (35 1-n-heptylamidino-3-methylurea (36) l- (n-tetracosanylamidino )urea 37 1-amidino-3 -n-tetracosanylurea (38) 1-n-docosanylamidino-S-methylthiourea (39) 1-[ (2-ethylhexyl) amidinolurea (40) l-amidino-Z- (2-ethylhexyl) urea Following are representative results obtained when the compounds prepared in accordance with the instant invention were tested in vitro by standard serial dilution procedures for bacteriostatic (Bs), bactericidal (Be), fungistatic (Fs), and fungicidal (Fc) properties; these results are expressed as minimum concentration of the test compound, in parts per million, required for no growth of the test organism. For example, in antibacterial tests, using Staphylococcus aureus 209, Samonella zyphosa Hop- 26 one-quarter pound per100 gallons of water was similarly Pa. aemy.

gin bsa applied to'tomato plants, 99 percent of the plants were Sal. typhqaa Cl. welchii Bs B B Be and Pseudomonas aeru Staph. aureua kins, Clostrz'dium welchii 21'], the results obtained were as follows Compound 0! Example number w mnenmmmmmn l Proteus mtlgari: ATCC 9920 was used instead of C7. welcMi. Escherichia coli was used instead of Sal. typhosa nmmmum mmmmmmammnwwma wmnnwnnm l 0 50050055 5555 5 7 7 m 11111 7 7 Mk nii n wmmw m o d n s e m o ow nm m mm fl i O ai b menul o ms m rwa m m Oma gc eP o .m b 8 n emfi$ v .m a am mb.. m a. tl wo e 3 .m mmme w m d f. O O n u mmm m w m w. am S m w ma mmm Ln v. i 1 a m mnwm nlnsl n m .mfl m am a x c a xHC W m m am e th w m m m ew m ammmwwnm smm m m m OS H.013C. O S 0 wn w m mwm n ma L. I y r. u a n m m m w e m m m a m m La mv m "r mm m w m m. m mm m wad N n m N .l. b Cd swa maiwpmmfim .3 m .m n mm u m n m u v. w a u Y WS m gii 0a m v amywm mme flmmm .mm m m m n m om u eso w o d e d m 1 g en o o l a c a C t h bomn r fl a .m u waw W m m mo m m m m e L. m m a m r m m %1 mm ma e no p mm m 0 m pm w w m m 5 0 5 0 5 4 5 5 6 6 J. 0 m m r H mm mmmmmmmmmmm m W "1'1 1 n h w n n P a u mm M. u S 00 0 a M F mmm mmmm mmmm mm m m m m m e H mm a n mm x t Mm .W m PM I. S u 5 5 0 an A F a wmmmmmmm mm mmmh m .w a 1 1 1 ri T. 0 0 O 0 F m mmmmmamm m a m .m m d m m 3 T a m mmmmm mmmm mmm fi 6 :0 1 Hwm abwm r. nb .m WSO m Iue 0 awn m w DD Dun mo sw n n H M000 2 .HHH DPS m n r\. 222 I m mm A1 BTHBB "01.2.. As CE 1 wmmmwwufiwuu wherein X is oxygen, Y is alkyl containing 1-18 carbon atoms, and Y' is alkyl containing 3-18 carbon atoms.

3. 1-hexylamidino-3-hexylurea, according to claim 2 wherein each of Y" and Y'" is hexyl.

4. l-heptylamidino-3-hexylurea, according to claim 2 wherein Y" is heptyl and Y is hexyl.

by X anthomonas When an aqueous solution of one pound of l-amidino- B-n-decylurea hydrobromide in gallons of Water was rayed onto the foilage of tomato plants 68 percent provesicatoria (bacterial spot). When the same compound at P tection was afforded against infection 3,798,269 27 28 5. 1 -hepty1amidino-3-heptylurea, according to claim OTHER REFERENCES Wherem each andY 1sliwptyl- Slotta et al., Berichte, vol. 63, pp. 212-216 1930 P,' X1% acwrding claim-2 I Junod, Helvetica Chimica Acta, vol. 35, p. 1670 1952 wherem each ofY andY 1S octyl' Dutta et al., J. Indian Chem. Soc., vol. 40, pp. 863

References Cited UNITED STATES PATENTS 2,631,152 3/1953 Ritter et a1 260-2391 FOREIGN PATENTS 954,114 4/ 1964 Great Britain.

BERNARD HELFIN, Primary Examiner M. W. GLYNN, Assistant Examiner 1 US. 01. X.R.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,79 9

Q DATED 1 March 19, 197A INVENTOR(S) Royal A. Cutler and Samuel Sohalit It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 21, line 35, "which melted at 50-61C." should read "which melted at 59-6lC.-. Column 25, line 12 on Chart, Compound example number 8A under amonella 'Iyphosa Bc 100", should read lOO--. Column 25, line 13 on Chart, Compound example number 8B under 0 Samonella Typhosa Bc 1,000", should read 1 OOO-. Column 25, line l t on Chart, Compound example number 9A under Staphyloccus aureus B0 1,000", should read 1 OOO- Column 25, line l t on Chart, Compound example number 9A under Samonella Typhosa Bc 1,000", should read 1,000-- Column 25, line L7 on Chart, Compound example number 38 under Samonella Typhosa Bs "20**", should read --50**--.

Signed and Scaled this 0 Thirteenth Day 0f September 1977 [SEAL] Attest:

RUTH C. MASON LUTRELLE F. PARKER Attesting Oflicer Acting Commissioner of Patents and Trademarks 

